重新定位 SARS-CoV-2 的治疗方法：基于植物的抗 HIV 化合物的虚拟筛选作为 COVID-19 病毒 RdRp 的可能抑制剂。

Repositioning Therapeutics for SARS-CoV-2: Virtual Screening of Plant-based Anti-HIV Compounds as Possible Inhibitors against COVID-19 Viral RdRp.

机构信息

Applied Plant Pathology Laboratory, Department of Studies in Botany, University of Mysore, Manasagangotri, Mysuru 570 006, Karnataka, India.

Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysuru 570 006, Karnataka, India.

出版信息

Curr Pharm Des. 2022;28(12):969-980. doi: 10.2174/1381612828666220428120939.

DOI:10.2174/1381612828666220428120939

PMID:35796443

Abstract

BACKGROUND

Coronavirus disease 2019 (COVID-19) has caused a global pandemic with a high mortality and morbidity rate worldwide. The COVID-19 vaccines that are currently in development or already approved are expected to provide at least some protection against the emerging variants of the virus, but the mutations may reduce the efficacy of the existing vaccines. Purified phytochemicals from medicinal plants provide a helpful framework for discovering new therapeutic leads as they have long been employed in traditional medicine to treat many disorders.

OBJECTIVE

The objectives of the study are to exploit the anti-HIV bioactive compounds against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through molecular docking studies and to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of potential compounds.

METHODS

Molecular docking was performed to study the interaction of ligands with the target sites of RdRp protein (PDB: 6M71) using AutoDock Vina. The ADMET properties of potential compounds were predicted using the pkCSM platform.

RESULTS

A total of 151 phytochemicals derived from the medicinal plants with recognized antiviral activity and 18 anti-HIV drugs were virtually screened against COVID-19 viral RdRp to identify putative inhibitors that facilitate the development of potential anti-COVID-19 drug candidates. The computational studies identified 34 compounds and three drugs inhibiting viral RdRp with binding energies ranging from -10.2 to -8.5 kcal/mol. Among them, five compounds, namely Michellamine B, Quercetin 3-O-(2'',6''-digalloyl)-beta-Dgalactopyranoside, Corilagin, Hypericin, and 1,2,3,4,6-Penta-O-galloyl-beta-D-glucose residues, bound efficiently with the binding site of RdRp. Besides, Lopinavir, Maraviroc, and Remdesivir drugs also inhibited SARS-CoV-2 polymerase. In addition, the ADMET properties of top potential compounds were also predicted in comparison to the drugs.

CONCLUSION

The present study suggested that these potential drug candidates can be further subjected to in vitro and in vivo studies that may help develop effective anti-COVID-19 drugs.

摘要

背景

2019 年冠状病毒病（COVID-19）在全球范围内造成了高死亡率和发病率，已成为全球性大流行。目前正在开发或已经批准的 COVID-19 疫苗有望提供针对病毒新兴变异体的至少部分保护，但这些突变可能会降低现有疫苗的效力。药用植物中的纯化植物化学物质为发现新的治疗方法提供了一个有用的框架，因为它们长期以来一直被用于传统医学来治疗许多疾病。

目的

本研究的目的是通过分子对接研究利用抗 HIV 生物活性化合物来对抗 SARS-CoV-2 RNA 依赖性 RNA 聚合酶（RdRp），并评估潜在化合物的吸收、分布、代谢、排泄和毒性（ADMET）特性。

方法

使用 AutoDock Vina 对配体与 RdRp 蛋白（PDB：6M71）靶位点的相互作用进行分子对接研究。使用 pkCSM 平台预测潜在化合物的 ADMET 特性。

结果

总共从具有公认抗病毒活性的药用植物中筛选出 151 种植物化学物质和 18 种抗 HIV 药物，以鉴定可促进开发潜在抗 COVID-19 药物候选物的假定抑制剂。计算研究确定了 34 种化合物和三种抑制病毒 RdRp 的药物，其结合能范围为-10.2 至-8.5 kcal/mol。其中，米歇林胺 B、槲皮素 3-O-（2''，6''-二没食子酰基）-β-D-半乳糖吡喃糖苷、柯里拉京、金丝桃素和 1,2,3,4,6-五-O-没食子酰基-β-D-葡萄糖残基 5 种化合物与 RdRp 的结合位点有效结合。此外，洛匹那韦、马拉维若和瑞德西韦药物也抑制了 SARS-CoV-2 聚合酶。此外，还预测了前 10 位潜在化合物的 ADMET 特性与药物进行比较。